Oxymorphone, generally administered in the form of its hydrochloride salt, is a potent semi-synthetic opiate analgesic, for the relief of moderate to severe pain, and has been approved for use since 1959. It can be administered as an injectable solution, suppository, tablet or extended release tablet. It is desirable to develop high purity forms of oxymorphone, especially with low levels of alpha-beta-unsaturated ketones, and a method for its synthesis.
Several methods for synthesizing oxymorphone from compounds isolated from the opium poppy or compounds derived therefrom are known, for example, starting from morphine, thebaine, or from oxycodone.
WO 2008/048711 describes a process for preparing oxymorphone wherein oripavine is oxidized to 14-hydroxymorphinone in a first step and 14-hydroxymorphinone is then reduced with hydrogen gas in the presence of a catalyst. Afterwards, oxymorphone is precipitated as a free base. The base is then further purified, and afterwards the HCl salt of oxymorphone is formed.
In US 2008/0146601, a process for the purification of a prepared raw oxymorphone is presented wherein the produced oxymorphone has a content of alpha-beta-unsaturated ketones <10 ppm. For the purification of the crude oxymorphone which is obtained in a similar fashion as in WO 2008/048711, a further hydrogenation of the crude oxymorphone is required. In this procedure, expensive high pressure equipment is needed for the hydrogenation step of the crude oxymorphone.
A further method for preparing oxymorphone is disclosed in US 2010/0048905. In the process described therein, the oxidation reaction of oripavine is carried out in the presence of a strong acid for an accelerated reaction, and then the reduction is carried out utilizing a hydrogen transfer reagent. A drawback of this process is that the strong acid utilized in the oxidation reaction has to be neutralized in the reduction step, leading to further by-products which affect the purity of the produced oxymorphone. Also, the reaction is slow, thereby limiting the productivity of the whole process.
There, thus, remains a need for methods which permit the formation of oxymorphone with low contamination of alpha-beta unsaturated ketones in a fast and efficient way which do not require a tedious and equipment-intensive purification treatment of crude oxymorphone.